This research project will study the role of epigenetic DNA regulation, and specifically of Cytosine methylation, in normal B-cell development and lymphomagenesis. The long-term objective for the project is to be able to subclassify the heterogeneous group of Diffuse Large B-cell Lymphomas (DLBCL) based on gene methylation signature into clinically relevant groups and to identify patients, which will be responsive to standard therapy and epigenetic therapy including demethylating agents. The specific aims include: a) identifying the epigenomic signatures in DLBCLs and subsets of normal B cells using DNA methylation and gene expression profiling, using epigenomic signatures to classify DLBCLs into prognostically and biologically relevant groups; b) identifying the molecular mechanism of normal and aberrant B-cell DNA methylation dependent gene silencing by studying the expression and biological functions of DNA methyltransferases and Methyl Binding proteins;identifying epigenomic signatures predictive of biological dependence on these factors and predictive of response to epigenetic therapy drugs, and testing the therapeutic value of targeting DNMTs and MBDs by using shRNA and small molecules in DLBCL cell lines and primary patient samples. The data will lead to predictive models of clinical and biological behavior of DLBCLs based on the integration of gene expression and epigenetic signatures, will identify epigenomic prognostic markers, identify genes and biological pathways which are responsible for neoplastic transformation of normal lymphocytes and will test the suitability of the epigenetic silencing machinery as potential therapeutic targets in DLBCL, which are most common and biologically heterogeneous group of lymphomas. Relevance to Public Health: This research project will study contribution of non-inheritable DNA modifications to the pathobiology of Lymphomas. We will identify prognostic markers in Diffuse Large B-cell Lymphomas, subclassify lymphomas based on epigenetic signatures and test novel therapies.